No abstract

No abstract

If genetic lesions were the sole reason of damage induced by ionizing radiation, an increase in the number of identical chromosome sets (polyploidy) may be expected to have a radioprotective effect. This effect is evident in terminally differentiated tissues when the reduction in remaining life span is used as the criterion. This effect is also evident in cells capable of proliferation if cytoplasmic growth during the period of mitotic delay is restricted and the criterion used is continuation of cell proliferation. Both instances demonstrate that polyploidy, in principle, can exert a radioprotective effect, although the genetic damage induced by a given dose increases in approximate proportion to ploidy. However, in mitotically active cells, without restrictions in cytoplasmic growth, differentiation enhancement dominates the effects of genetic lesions, and polyploidy does not protect. Enhancement of differentiation causes damage by eliminating amplification divisions normally passed through by cell progenies before terminal differentiation, thus reducing the number of differentiated cells produced. From its dependence on excess cytoplasmic growth it is concluded that the phenomenon is caused by the interference of ionizing radiation with a mechanism that provides intracellular signals needed to coordinate molecular interactions involved in the control of cell differentiation. This conclusion corresponds to experiments that suggest that intracellular control of differentiation depends on an increase in the ratio of essential cytoplasmic constituents, probably mitochondrial genomes, per nuclear genome. The action of chemical differentiation enhancing agents is similar and an outline of probable mechanisms is presented. Regarding late radiation damage it is concluded that non-specific genetic lesions can enhance differentiation by permanently prolonging the cell cycle, which causes an increased cytoplasmic growth rate per cycle. In this case polyploidy cannot protect because the induced genetic lesions are proportional to ploidy. Both the duration of mitotic delay, and the extent of genetic lesions increase with chromosome size, thus explaining the correlation between interphase chromosome volume and radio-sensitivity. Lack of substantial radioprotecting effect of polyploidy in neoplastically transformed mammalian cells indicates residual capabilities to cease cell proliferation by mechanisms related to terminal differentiation, thus offering clues to tumour therapy.

For the measurement of long-term residual radiation effect in the murine hematopoietic system a test system was developed that quantifies the proliferation ability of progeny of spleen repopulating cells by the proliferation factor (PF). The PF expresses the ratios of 125IUdR incorporation in the recipient spleens at days 3 and 5 following cell transfusion, thus measuring the relative increase in number of proliferating cells. Following 500 rad whole-body gamma irradiation, PF recovered up to 6 months and remained thereafter, on the average, at 80% of control. Recovery of the number of 7-day CFU-S was similar to recovery of PF. Various studies were aimed at elucidating the reasons for reduction in PF. Loss of incorporated 125IUdR activity from spleens between days 3 and 5 after cell transfusion indicates loss of mature labeled cells. When the doubling time of proliferating cells of CFU-S progeny (td) is corrected for cell loss, td for control bone marrow approaches mitotic cycle time in normal bone marrow as was found elsewhere. Following 500 rad, both cell loss and td were initially increased and recovered in parallel with PF and number of CFU-S. Reduction of PF could be brought about by radiation-induced increase in transient CFU-S with the consequence of increased loss of mature cells between days 3 and 5. This possibility was excluded by the observation that 1 year after 500 rad the number of colonies per spleen did not decrease from day 7 to day 12 after cell transfusion, as was expected from a higher proportion of transient CFU-S, but increased more than in the controls. Measurement of these 12-day colonies showed a significantly reduced size. Average progeny from irradiated CFU-S, apparently, grow more slowly. It is concluded that sublethal injury resides in stem cells, increases mitotic cycle time, and causes precocious loss of cells from spleens probably by enhanced differentiation and maturation due to interference with endocellular control of cell proliferation and differentiation. Probably the observed recovery proceeds via replacement of injured stem cells by less injured or normal stem cells.